Fatigue and circadian rhythm in non-cirrhotic primary biliary cholangitis: An exploratory comparison with primary sclerosing cholangitis and healthy controls

Abstract

BACKGROUND

Fatigue is common and debilitating in primary biliary cholangitis (PBC) without clear relation to disease stage; mechanisms remain unclear. Circadian disruption is reported in end-stage liver disease, but evidence in non-cirrhotic PBC, and links to fatigue, is scarce.

AIM

To investigate the severity and phenotype of fatigue, daytime sleepiness, and chronotype in non-cirrhotic PBC, and compare findings with matched healthy controls (HC) and non-cirrhotic primary sclerosing cholangitis (PSC).

METHODS

Participants completed the Fatigue Impact Scale, Epworth Sleepiness Scale, and Morningness-Eveningness Questionnaire Self-Assessment. Demographics, sleep habits, employment, and fatigue subtype (mental vs muscular) were recorded. In PBC/PSC, PBC-40 fatigue/itch domains and disease characteristics were analyzed. Group comparisons and multivariable models evaluated associations of fatigue phenotype and chronotype with demographic/disease variables.

RESULTS

We enrolled 152 individuals: 61 PBC, 30 PSC, and 61 HC. Global fatigue scores did not differ across groups. Muscular fatigue predominated in PBC/PSC, whereas HC more often reported mental fatigue; this pattern persisted after stratifying by employment and sex. In adjusted analyses, HC had lower odds of muscular fatigue than PBC [odd ratio (OR) = 0.30, 95% confidence interval (CI): 0.14-0.63; P = 0.002]; PSC did not differ from PBC (OR = 1.25, 95%CI: 0.44-3.71; P = 0.681). Older age independently increased the odds of muscular fatigue (OR = 1.04 per year, 95%CI: 1.01-1.07; P = 0.016). Daytime sleepiness was low and similar between groups. Morningness-Eveningness Questionnaire Self-Assessment scores clustered in the intermediate range; age, not disease, predicted greater morningness.

CONCLUSION

In non-cirrhotic PBC, fatigue shows a predominantly muscular phenotype independent of demographics/occupation and decoupled from conventional disease metrics. Chronotype and daytime alertness appear largely preserved, with age driving modest morningness. Findings support integrating fatigue phenotyping into assessment, prioritizing muscle-targeted interventions, and using carefully selected controls and objective endpoints in future studies.

Keywords: Chronotype; Daytime sleepiness; Cholestatic disorders; Mental; Muscular; Primary biliary cholangitis; Primary sclerosing cholangitis

Core Tip: In non-cirrhotic primary biliary cholangitis, fatigue burden is similar to healthy controls and primary sclerosing cholangitis, but its phenotype is predominantly muscular (approximately 69%), independent of sex, age-adjusted employment, or routine disease metrics; daytime sleepiness and sleep duration are low/normal, and chronotype clusters in the intermediate range, with age - not disease - driving greater morningness. Primary sclerosing cholangitis shows a similar (weaker) direction of effect. These findings support routine fatigue phenotyping and muscle-focused interventions over cholestasis-directed therapies, and argue for objective endpoints (e.g., ³¹phosphorus magnetic resonance spectroscopy, actigraphy) in future trials.